FORM2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention: IMPROVED PROCESSES
2. Applicant(s):

(a) NAME: MVLAN INDIA PRIVATE LIMITED
(b) NATIONALITY: An Indian Company.
(c) ADDRESS: Plot 1A/2, MIDC. Industrial Estate, Taloja,
Panvel, District Raigad, Maharashtra-410208, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed :

Field of the Invention
The present invention relates to the active pharmaceutical ingredient, Dipyridamole. In particular, it relates to efficient processes for the preparation of Dipyridamole which are amenable to large-scale commercial production and provides the required product with improved yield and purity. The present invention also relates to a novel crystallization method for the purification of Dipyridamole.
Background of the Invention
Dipyridamole, represented by structural formula (I), possesses platelet aggregation inhibiting, anti-thrombotic and vasodilator properties and it is marketed as an antiplatelet therapy for the treatment and prevention of disorders such as thromboembolisms.

A process for the preparation of Dipyridamole, disclosed in US patent 3031450, involves the reaction of 2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine with diethanol-amine (see Scheme 1). The preparation of 2,6-dichloro-4,8-dipiperidinopyrimido(5,4-d)pyrimidine is also reported in US 3031450 and is incorporated herein by reference. The reaction to prepare Dipyridamole does not employ an additional reaction solvent and is a neat mixture of the two reactants carried out at a very high temperature of 190 to 195 °C. The process also involves a

cumbersome workup process to isolate Dipyridamole as the crude product obtained is a pasty mass which needs decantation of the mother liquor and further purification. This decantation process is not practical on commercial scale.

A similar process for the production of Dipyridamole is described in patent DD 117456 wherein the reaction conditions exemplified are heating 2,6-dichIoro-4,8-dipiperidino-pyrirnido(5,4-d)pyrirnidine and diethanolamine at 155 to 160 °C under vacuum. However, this process again requires high temperature which leads to the formation of impurities.
A process for the preparation and purification of Dipyridamole is disclosed in patent DE 1812918, wherein 2,6-dichloro-4,8-dipiperidinopyrimido(5,4~d)pyrimidine and diethanol-amine are heated to 150 to 200 °C. After completion of the reaction, the reaction mixture is dissolved in chloroform, which is further separated into an upper layer of diethanolamine and its hydrochloride. The chloroform solution obtained is separated and reduced to dryness after stirring with water. This process also requires high temperature which can lead to formation of impurities. In addition, the solvent

used for isolation of Dipyridamole, chloroform, is inconvenient as it is a restricted solvent and its permitted limit in the final marketed Dipyridamole is very low.
A similar process, wherein Dipyridamole is manufactured by the reaction of diethanolamine with 2,6-dichloro-4,8-dipiperidinopyrimido(5,4-d)pyrimidine is disclosed in patent RO 104718. However, this process again requires high temperatures of 180 to 200 °C, which leads to the formation of impurities and consequently, the yield of the final product is very low (58%) with a purity of less than 98%.
A process is disclosed in patent DD 1 15670, wherein the purification of Dipyridamole involves refluxing it in butyl acetate, AcOBu, for 2 hours in the presence of an equal amount of silica gel or by column chromatography on silica gel. However, the purification by column chromatography is not economical and not feasible at industrial scale.
The processes described above to prepare Dipyridamole do not employ an additional reaction solvent but involve neat mixtures of the two reactants, 2,6-dichloro-4,8-dipiperidinopyrimido(5,4-d)pyrimidine and diethanolamine, which are heated at very high temperatures. The use of neat reaction mixtures and/or high temperatures means that it is very difficult to control the levels of impurities formed.
Another process for the preparation of Dipyridamole, disclosed in patent application WO 2007/080463Al, involves reacting diethanolamine with 2,6-dichloro-4,8-dipiperidinopyrimido(5,4-d)pyrimidine in a solvent selected from the group consisting of 1 -methyl-2-pyrrolidinone, sulpholane and polyethylene glycol. However, the exemplified reaction temperatures are very high at 190 to 200 °C and the HPLC purity of the crude Dipyridamole is reported to be only 90-94%. A purification method is disclosed using a ketonic solvent and an aqueous alcoholic

solvent OT a mixture thereof. Even though the process disclosed in this patent application uses a solvent in the reaction, the temperature of reaction is still very high and the purification in ketonic solvent is reported at high temperature (100 to 120 °C). The HPLC purity after purification is reported as only 99.0-99.5%.
As discussed above, all the processes disclosed in the prior art for the preparation of Dipyridamole suffer from serious disadvantages with respect to commercial production. The prior art synthetic and purification processes employ high temperatures in the preparation of Dipyridamole which lead to inefficiency and high processing costs. The high temperatures also lead to higher levels of impurities being formed during manufacture with the consequence that further cumbersome and expensive purification procedures are required.
Considering the importance gained by Dipyridamole as a commercial medicine, there is a great need for developing simple, inexpensive, good yielding and commercially feasible processes for the manufacturing of high quality Dipyridamole.
Object of the Invention
Therefore, there is a need for an improved process for the synthesis and purification of Dipyridamole which provide commercial quantities of products conveniently, economically and with high yield and purity. A further objective is to provide extremely pure Dipyridamole substantially free of all impurities.
Summary of the Invention
The term Dipyridamole as used herein throughout the description and claims means Dipyridamole and/or any salt, solvate or isomer thereof unless specified otherwise.
A first aspect of the present invention provides a process for the preparation of Dipyridamole comprising reacting 2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)-

pyrimidine with diethanolamine at a temperature below 130 °C. Preferably, the reaction temperature is between about 100 °C and below 130 °C, preferably between about 100 °C and about 125 °C, preferably between about 110 °C and about 125 °C, preferably between about 110 °C and about 120 °C, preferably between about 110 °C and about 115 °C and most preferably between about 113 °C and about 115 °C.
Preferably, in a process according to the first aspect of the present invention, the reaction mixture is a neat mixture of the two reactants, 2,6-dichloio-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine and diethanolamine, with no additional reaction solvent.
Preferably, the 2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine is dissolved in the diethanolamine.
Alternatively, in a process according to the first aspect of the present invention, an additional reaction solvent may be used. Preferably, the additional reaction solvent is selected from a polar aprotic solvent, preferably, dimethyl sulfoxide.
Optionally, the intermediate compound, 2-chloro-6-diethanolamino-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine is isolated before being reacted with diethanolamine to form Dipyridamole.
A particularly preferred process for the preparation of Dipyridamole according to the present invention comprises the steps of:
a) providing a mixture of 2,6-dichloro-4,8-dipiperidinopyrimido-(5,4-d)- pyrimidine and diethanolamine
b) heating the mixture from step a)
c) adding ethanol to the solution from step b)
d) adding toluene to the solution from step c)
e) adding water to the solution from step d)

f) cooling the mixture from step e)
g) isolating the resulting solid.
Another particularly preferred process for the preparation of Dipyridamole according to the present invention comprises the steps of:
a) providing a mixture of 2,6-Dichloro-4,8-dipiperidinopyrimido-(5,4-d)pyrimidine, diethanolamine and dimethyl sulfoxide
b) heating -the mixture from step a)
c) adding acetone to the solution from step b)
d) adding water to the solution from step c)
e) cooling the mixture from step d)
f) isolating the resulting 2-chloro,6-diethanolamino-4,8-dipiperidino-pyrimi do(5,4 -d)pyrimidi ne
g) Drying the solid
h) providing a mixture of 2-chloro,6-diethanolamino-4,8-dipip-
eridinopyrimido(5,4-d)pyrimidine and diethanolamine i) heating the mixture from step h) j) adding ethanol to the solution from step i) k) adding toluene to the solution from step j) 1) adding water to the solution from step k) m) cooling the mixture from step 1) n) isolating the resulting solid
A second aspect according to the present invention provides a process for the purification of Dipyridamole comprising the steps of:
a) heating a mixture of crude Dipyridamole and diethanolamine to get a clear solution,
b) adding ethanol to the solution from step a)
c) adding toluene to the solution from step b)

d) adding water to the solution from step c)
e) cooling the mixture from step d)
f) isolating the resulting solid.
A third aspect according to the present invention provides a pharmaceutical composition comprising Dipyridamole prepared by a process according to the first or second aspect of the present invention.
A fourth aspect according to the present invention provides the use of Dipyridamole, prepared by a process according to the first or second aspect of the present invention, in the preparation of a medicament for the treatment of platelet aggregation.
A fifth aspect according to the present invention provides Dipyridamole with a purity of greater than 99%, preferably with a purity greater than 99.5%, more preferably greater than 99.8% and most preferably greater than 99.9%.
A sixth aspect according to the present invention provides Dipyridamole comprising less than about 0.1% of one or more of impurities A to F, preferably comprising less than about 0.05% of one or more of impurities A to F. (See Figure 1 for the structures of impurities A to F).
A seventh aspect according to the present invention provides Dipyridamole prepared according to the first or second aspects of the present invention with a chemical purity of more than 99.5%, preferably more than 99.8% and most preferably more than 99.9%.
An eighth aspect according to the present invention provides Dipyridamole prepared according to the first or second aspects of the present invention comprising less than

0.1% of one or more of impurities A to F, preferably less than 0.05% of one or more of impurities A to F
Detailed Description of the Invention
The present invention provides improved processes for the preparation of Dipyridamole, particularly for the preparation of highly pure Dipyridamole. The improved processes are simple, inexpensive, good yielding and can be easily adopted for commercial production with a high degree of consistency and reproducibility.
The present inventors have surprisingly discovered that the use of lower reaction temperatures for the reaction of diethanolamine with 2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine to form Dipyridamole still affords complete reaction in a convenient time scale but markedly reduces the levels of impurities formed in the reaction. The use of the lower reaction temperatures in the process according to the invention significantly controls the formation of the impurities. Crude Dipyridamole having a purity of greater than 98% was obtained by this process.
The present inventors have also developed a low temperature process of converting 2,6-dichloro-4,8-dipiperidinopyrimido(5,4-d)pyrimidine to the mono substituted product, 2-chloro-6-diethanolamino-4,8-dipiperidinopyrimido(5,4-d)pyrimidine, by treating 2,6-dichloro-4,8-dipiperidinopyrimido(5,4-d)pyrimidine with diethanolamine in a solvent. The mono-substituted intermediate is then converted to Dipyridamole by reacting it with diethanolamine at low temperature. The isolation of 2-chloro-6-diethanolamino-4,8-dipiperidinopyrimido(5,4-d)pyrimidine, and further conversion to Dipyridamole at lower temperature, in a process according to the invention, controls the formation of significant levels of impurities. Crude Dipyridamole having a purity of greater than 98% was obtained by this process.

The levels of impurities in the crude product obtained, in the processes of the present invention, are significantly lower than in prior art process. As a consequence, work up and purification procedures become far more convenient than those disclosed in the prior art and Dipyridamole with very high purity is easily and conveniently obtained.
A low temperature purification method to obtain Dipyridamole with more than 99.8% purity has also been developed. The purification is achieved by using a novel solvent system, preferably comprising diethanolamine, ethanol, toluene and water. The reaction conditions and further purification method controls the formation of all known and unknown impurities to well below acceptable levels but employ temperatures much lower than prior art crystallization procedures.
In the processes according to the present invention 2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine is added to diethanolamine. In preferred embodiments the mixture is heated to substantially dissolve the 2,6-dichloro-4,8-dipiperidinopyrimido(5,4-d)pyrimidine. Preferably, this temperature is about 110-125°C, most preferably about 113-115°C.
Therefore, the processes of the present invention comprise improved and defined process parameters for the manufacturing of Dipyridamole wherein formation of impurities are precisely controlled and minimized.
In addition, the processes of the present invention offer simpler work-up and/or purification procedures with optimum conditions for improved yield and quality with minimum contamination with process impurities. The improved process can be easily adapted on commercial scale as an efficient and convenient process.

Advantageously, the processes of the present invention avoid column chromatography purification techniques thereby making the processes simpler and more adaptable for large scale commercial production.
Further aspects of the present invention provide Dipyridamole of greater than 99% purity (as measured by HPLC). Preferably the Dipyridamole of the present invention has a purity of greater than 99.5%, more preferably greater than 99.8% and most preferably greater than 99.9%.
The high quality Dipyridamole prepared by the present invention can be used for the preparation of a pharmaceutical composition to use in the manufacture of medicament as anti-platelet therapy.
A preferred embodiment of the present invention, illustrated in Scheme 2, provides a process for the preparation of Dipyridamole comprising reacting 2,6-DichIoro-4,8-dipiperidinopyrimido(5,4-d)pyrimidine with diethanolamine at 113-115 °C. This reaction temperature is significantly lower than the prior art processes to prepare Dipyridamole.


Another preferred embodiment of the present invention, illustrated in Scheme 3, also provides a process for preparation of Dipyridamole by the reaction 2,6-Dichloro-4,8-dipiperidinopyrimido-(5,4-d)pyrimidine with diethanolamine in dimethylsulfoxide at 120-125 °C to afford the monosubstituted intermediate, 2-chloro-6-diethanolamino-4,8-dipiperidinopyrimido(5,4-d)pyrimidine, which is isolated and then further converted to Dipyridamole by heating in diethanolamine at 113-115 °C.
Although, the solvent used in this aspect of the present invention is preferably dimethylsulfoxide (DMSO), other solvents can alternatively be used. Preferred alternative solvents are other polar aprotic solvents, such as dimethylformamide (DMF), dimethyl acetamide (DMA) or N-methyl-2-pyrrolidinone (NMP). Alternatively, hydrocarbon solvents can be used. Preferred hydrocarbon solvents are aromatic solvents such as toluene or xylene.

The crude Dipyridamole obtained, in preferred embodiments of the present invention or by any other processes, is preferably purified by using a novel solvent system consisting of diethanolamine, ethanol, toluene and water in a single step to afford highly pure Dipyridamole.
In preferred embodiments of the present invention, pure Dipyridamole is obtained free of one or more of impurities A-F. The structures of impurities A-F are illustrated in Figure 1.

A particularly preferred embodiment of the first aspect of the present invention comprises the following steps:
a) providing a mixture of 2,6-Dichloro-4,8-dipiperidinopyrimido-(5,4-d) pyrimidine and diethanolamine
b) heating the mixture from step a)
c) adding ethanol to the solution from step b)
d) adding toluene to the solution from step c)
e) adding water to the solution from step d)
f) cooling the mixture from step e)
g) isolating the resulting solid.
Preferably, the mixture from step a) is heated to between about 110 to 125 °C, preferably the mixture is heated to about 113 to 115°C. Preferably, ethanol is added to the mixture from step b) at about 60 to 80°C, more preferably at about 75-80°C. Preferably, toluene is added to the mixture from step c) at about 60-80°C, more preferably at about 70-75°C. Preferably, water is added to the mixture from step d) at about 50-70°C, more preferably at about 60-65°C. preferably, the mixture from step e) is cooled at about 20-40°C, more preferably at about 25°C. Preferably, the solid from step c) is isolated by filtration and preferably the solid is further washed, most preferably with water. Preferably, the solid is further dried, preferably under vacuum. Although, the two organic solvents used in this aspect of the present invention are preferably ethanol and toluene, other solvents can alternatively be used. Preferred alternative solvents are other C1-C6 alkyl alcohols instead of ethanol and other hydrocarbon solvents instead of toluene, particularly aromatic hydrocarbon solvents, such as xylene.
Another preferred embodiment of the first aspect of the present invention comprises the following steps:

a) providing a mixture of 2,6-Dichloro-4,8-dipiperidinopyrimido-(5,4-d)pyrimidine, diethanolamine in dimethylsulfoxide
b) heating the mixture from step a)
c) adding acetone to the solution from step b)
d) adding water to the solution from step c)
e) cooling the mixture from step d)
f) isolating the resulting solid of 2-chloro,6-diethanolamino-4,8-
dipiperidinopyrimido(5,4-d)pyrimidine
g) drying the solid
h) providing a mixture of 2-chloro,6-diethanoIamino-4,8-dipiperidinopyrimido(5,4-d)pyrimidine, diethanolamine and dimethylsulfoxide
i) heating the mixture from step
j) adding ethanol to the solution from step i)
k) adding toluene to the solution from step j)
1) adding water to the solution from step k)
m) cooling the mixture from step 1)
n) isolating the resulting solid.
Preferably, the mixture from step a) is heated to between about 110 and 130°C, more preferably the mixture is heated to about 120-125°C. Preferably, acetone is added to the mixture from step b) at about 45-60X, more preferably at about 55-60°C. Preferably, water was added to the mixture from step c) at about 50 to 70°C, more preferably at about 55-60°C. Preferably, the mixture from step d) is cooled at about 20-40°C, more preferably at about 25°C. Preferably, the resultant solid from step e) is isolated in step f) by filtration and preferably the solid is further washed, most preferably with water. Preferably, the solid is further dried, preferably under vacuum. Preferably, the mixture from step h) is heated to between about 110 and 125°C, more preferably the mixture is heated to about 113-115°C. Preferably, the ethanol is added

to the mixture from step i) at about 60-80°C, more preferably at about 75-80°C. Preferably, toluene is added to the mixture from step j) at about 60-80°C, more preferably at about 70-75°C. Preferably, water is added to the mixture from step k) at about 50-700C, more preferably at about 60-65°C. Preferably, the mixture from step 1) is cooled at about 20-40°C, more preferably at about 25°C. Preferably, the resultant solid from step m) is isolated by filtration and preferably the solid is further washed, most preferably with water. Preferably, the solid is further dried, preferably under vacuum. Although, the four organic solvents used in this aspect of the present invention are preferably DMSO, acetone, ethanol and toluene, other solvents can alternatively be used. Preferred alternative solvents are: instead of DMSO - other polar aprotic solvents, such as dimethylformamide (DMF), dimethylacetamide (DMA) or N-methyl-2-pyrrolidinone (NMP) or hydrocarbon solvents such as aromatic solvents such as toluene or xylene; instead of acetone - other C3-C8 alkyl ketones or alkyl nitriles, such as acetonitrile; instead of ethanol - other C1-C6 alkyl alcohols; and instead of toluene other hydrocarbon solvents, particularly aromatic hydrocarbon solvents, such as xylene.
A preferred embodiment of the second aspect of the present invention comprises the following steps:
a) heating a mixture of crude Dipyridamole and diethanolamine to obtain a clear solution,
b) adding ethanol to the solution from step a)
c) adding toluene to the solution from step b)
d) adding water to the solution from step c)
e) cooling the mixture from step d)
f) isolating the resulting solid.
Preferably the mixture from step a) is heated to between about 60 and 90°C, more preferably the mixture is heated to about 75-80°C. Preferably, ethanol is added to the

mixture from step a) at about 60-80°C, preferably at about 75-80°C. Preferably, toluene is added to the mixture from step b) at about 60-80°C, more preferably at about 70-75°C. Preferably, water is added to the mixture from step c) at about 50-70°C, more preferably at about 70-75°C. Preferably, the mixture from step d) is cooled at about 20-40°C, more preferably at about 25°C. Preferably, the resultant solid from step e) is isolated by filtration and preferably the solid is further washed, most preferably with water. Preferably, the solid is further dried, preferably under vacuum. Although, the two organic solvents used in this aspect of the present invention are preferably ethanol and toluene, other solvents can alternatively be used. Preferred alternative solvents are other C1-C6 alkyl alcohols instead of ethanol and other hydrocarbon solvents instead of toluene, particularly aromatic hydrocarbon solvents, such as xylene.
A further aspect of the present invention provides Dipyridamole comprising less than about 0.1%, preferably less than about 0.05%, of Impurities A-F and/or any other unknown impurities.
The Dipyridamole prepared by the improved processes according to the present invention can be easily converted into any suitable salt if required. The highly pure Dipyridamole can be converted into a salt, if required, with chemical purity > 99.9%.
Dipyridamole obtained by the disclosed process is > 99.8% pure by HPLC analysis and more preferably > 99.9% pure by HPLC analysis.
Further details of the invention are illustrated below in the following non-limiting examples

Examples Example 1
Diethanolamine (10 Vol) and 2,6-dichloro-4,8-dipiperidinopyrimido(5,4-d)pyrimidine (leq) were mixed at 25-30 °C, stirred for lOmin and then heated at 113-115°C for 45-48 hours. After completion of the reaction, the mixture was cooled to 75-80°C. Ethanol (5Vol) was added at 75-80°C and the mixture was stirred at 75-80 °C for lOmin, Toluene (10Vol) was added at 70-750C and the mixture was stirred at 70-75 °C for 15min. Purified water (15Vol) was added and the mixture was stirred at 60-65 °C for 30min. The mixture was then cooled and stirred at 25-30 °C for 30min. The precipitated solid was filtered and washed with purified water before drying at 75-80°C under reduced pressure afforded crude Dipyridamole as a yellow crystalline solid.
Yield - 80-85% w/w HPLC purity = >98%
Example 2
Stage 1: Preparation of 2-chIoro-6-diethanolaminO-4,8-
dipiperidinopyrimido(5,4-d)pyrimidine
Diethanolamine (3eq) and 2,6-dichloro-4,8-dipiperidinopyrimido(5,4-d)pyrirnidine (leq) were added to dimethylsulfoxide (lOVol) at 25-30°C, stirred for lOmin and then heated at 120-125°C for 4-5 hours. After completion of the reaction, the reaction mixture was cooled to 55-60°C. Acetone (5Vol) was added at 55-60°C and the mixture was stirred at 55-60 °C for lOmin. Water (l5Vol) was added and the mixture was stirred at 50-55°C for 15min. The mixture was cooled to 25-30 °C and stirred at 25-30 C for 30min. The precipitated solid was filtered and washed with purified water (2*5Vol) and dried at 75-80°C under reduced pressure to afford crude 2-chloro-6-diethanolarnino-4,8-dipiperidinopyrimido(5,4- d)pyrimidine as a yellow crystalline solid. Yield = 110-120% w/w

HPLC purity = >96%
Stage 2: Preparation of Crude Dipyridamole
Diethanolamine (lOVol) and 2-chloro-6-diethanolamino-4,8-dipiperidinopyrimido (5,4- d)pyrimidine (leq) were mixed at 25-30 °C, stirred for lOmin and heated at 113-115 °C for 45-48 hours. After completion of the reaction, the mixture was cooled to 75-80°C. Ethanol (5Vol) was added and the mixture was stirred at 75-80°C for lOmin. Toluene (lOVol) was added and the mixture was stirred at 70-75°C for 15min. Purified water (15Vol) was added and the mixture was stirred at 60-65 C for 30min. The mixture was cooled to 25-30 °C and stirred for 30min. The precipitated solid was filtered, washed with purified water (2*5Vol) and dried at 75-80°C under reduced pressure to afford crude Dipyridamole as a yellow crystalline solid. Yield = 95-97% w/w HPLC purity = >98%
Example 3
Crystallization of crude Dipyridmole
Crude Dipyridamole and diethanolamine (8 Vol with respect to crude Dipyridamole) were stirred together at 25-30 °C for lOmin and then heated to 80°C. The clear solution was cooled to 75-80°C, ethanol (5VoI) added and the mixture was stirred at 75-80°C for 10 min. Toluene (lOVol) was added and the mixture was stirred at 70-75°C for 15min. The mixture was cooled to 25-30°C and filtered. The filtrate was heated to 70-75 °C and purified water (15Vol) was added and the mixture was stirred at 60-65 °C for 30min before cooling to 25-30 °C with stirring for 30min. The precipitated solid crude Dipyridamole was filtered and washed with purified water (2*5Vol), dried at 75-80°C under reduced pressure to afford the product as a yellow crystalline solid. Yield = 90-95% HPLC purity = >99.9%

Claims
1. A process for the preparation of Dipyridamole comprising reacting 2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine with diethanolamine at a temperature below 130 °C.
2. A process according to claim 1 wherein the reaction temperature is between about 100 °C and below 130 °C.
3. A process according to claim 2 wherein the reaction temperature is between about 100 °C and about 125 °C.
4. A process according to claim 3 wherein the reaction temperature is between about 110 °C and about 125 °C.
5. A process according to claim 4 wherein the reaction temperature is between about 110 °C and about 120 °C
6. A process according to claim 5 wherein the reaction temperature is between about 110 °C and about 115 °C.
7. A process according to claim 6 wherein the reaction temperature is between about 113 °C and about 115 °C
8. A process according to any preceding claim wherein the reaction mixture is a neat mixture of the two reactants, 2,6-dichloro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine and diethanolamine, with no additional reaction solvent.
9. A process according to claim 8 wherein the 2,6-dichIoro-4,8-dipiperidino-pyrimido(5,4-d)pyrimidine is dissolved in the diethanolamine.
10. A process according to any preceding claim wherein an additional reaction solvent is used.
11. A process according to claim 10 wherein the additional reaction solvent is selected from a polar aprotic solvent.
12. A process according to claim 11 wherein the solvent is dimethyl sulfoxide.

13. A process according to claim 10 to 12 wherein the intermediate compound, 2-chloro-6-diethanolamino-4,8-dipiperidinopyrimido(5,4-d)pyrimidine is isolated before being reacted with diethanolamine to form Dipyridamole.
14. A process for the preparation of Dipyridamole comprising the steps of:
a) providing a mixture of 2,6-dichloro-4,8-dipiperidinopyrimido-(5,4-d)-
pyrimidine and diethanolamine
b) heating the mixture from step a)
c) adding ethanol to the solution from step b)
d) adding toluene to the solution from step c)
e) adding water to the solution from step d)
f) cooling the mixture from step e)
g) isolating the resulting solid.
15. A process for the preparation of Dipyridamole comprising the steps of:
a) providing a mixture of 2,6-Dichloro-4,8-dipiperidinopyrimido-(5,4-d)pyrimidine, diethanolamine and dimethylsulfoxide
b) heating the mixture from step a)
c) adding acetone to the solution from step b)
d) adding water to the solution from step c)
e) cooling the mixture from step d)
f) isolating the resulting 2-chloro,6-diethanolamino-4,8-dipiperidino-pyrimido(5,4- d)pyrimidine
g) drying the solid
h) providing a mixture of 2-chloro,6-diethanolamino-4,8-
dipiperidinopyrimido(5,4- d)pyrimidine and diethanolamine i) heating the mixture from step h) j) adding ethanol to the solution from step i) k) adding toluene to the solution from step j) 1) adding water to the solution from step k) m) cooling the mixture from step 1)

n) isolating the resulting solid
16. A process for the purification of Dipyridamole comprising the steps of
a) heating a mixture of crude Dipyridamole and diethanolamine to get a clear solution,
b) adding ethanol to the solution from step a)
c) adding toluene to the solution from step b)
d) adding water to the solution from step c)
e) cooling the mixture from step d)
f) isolating the resulting solid.
17. A pharmaceutical composition comprising Dipyridamole prepared by a process according to any preceding claim.
18. The use of Dipyridamole, as prepared by the processes according any of claims 1 to 16, in the preparation of a medicament for the treatment of platelet aggregation.
19. Dipyridamole with a purity of greater than 99%.
20. Dipyridamole according to claim 19 with a purity greater than 99.5%.
21. Dipyridamole according to claim 20 with a purity greater than 99.8%.
22. Dipyridamole according to claim 21 with a purity greater than 99.9%.
23. Dipyridamole comprising less than about 0.1% of one or more of impurities A to F.
24. Dipyridamole according to claim 23 comprising less than about 0.05% of one or more of impurities A to F.
25. Dipyridamole prepared according to any one of claims 1 to 16 with a chemical purity of more than 99.5%.
26. Dipyridamole according to claim 25 with a chemical purity of more than 99.8%
27. Dipyridamole according to claim 26 with a chemical purity of more than 99.9%.
28. Dipyridamole prepared according to any one of claims 1 to 16 comprising less than 0.1% of one or more of impurities A to F.

29. Dipyridamole according to claim 28 comprising less than 0.05% of one or more of impurities A to F